Tramadol - Drug Information - UpToDate

1/11/22, 7:00 Tramadol: Drug information - UpToDate
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Tramadol: Drug information
Copyright 1978-2022 Lexicomp, Inc. All rights reserved.
Contributor Disclosures
(For additional information see "Tramadol: Patient drug information" and see "Tramadol: Pediatric drug information")
For abbreviations, symbols, and age group definitions used in Lexicomp ( show table)
ALERT: US Boxed Warning

Risk of medication errors:
Ensure accuracy when prescribing, dispensing, and administering tramadol oral solution. Dosing errors due to confusion between
mg and mL can result in accidental overdose and death.
Addiction, abuse, and misuse:
Tramadol exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and
death. Assess each patient's risk prior to prescribing tramadol, and monitor all patients regularly for the development of these
behaviors and conditions.
Opioid analgesic Risk Evaluation and Mitigation Strategy (REMS):
To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug
Administration (FDA) has required a REMS for these products. Under the requirements of the REMS, drug companies with approved
opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers
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are strongly encouraged to complete a REMS-compliant education program; counsel patients and/or their caregivers, with every
prescription, on safe use, serious risks, storage, and disposal of these products; emphasize to patients and their caregivers the
importance of reading the Medication Guide every time it is provided by their pharmacist; and consider other tools to improve
patient, household, and community safety.
Life-threatening respiratory depression:
Serious, life-threatening, or fatal respiratory depression may occur with use of tramadol. Monitor for respiratory depression,
especially during initiation of tramadol or following a dose increase. Instruct patients to swallow tramadol capsules and extended-
release tablets intact, and not to split, break, chew, crush, or dissolve the contents of the capsules or extended-release tablets to
avoid exposure to a potentially fatal dose of tramadol.
Accidental ingestion:
Accidental ingestion of tramadol, especially by children, can be fatal.
Ultra-rapid metabolism of tramadol and other risk factors for life-threatening respiratory depression in children:
Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported followed
tonsillectomy and/or adenoidectomy; in at least 1 case, the child had evidence of being an ultra-rapid metabolizer of tramadol due
to a CYP450 2D6 polymorphism. Tramadol is contraindicated in children <12 years of age and in children <18 years of age following
tonsillectomy and/or adenoidectomy. Avoid the use of tramadol in adolescents 12 to 18 years of age who have other risk factors
that may increase their sensitivity to the respiratory depressant effects of tramadol.
Neonatal opioid withdrawal syndrome:
Prolonged use of tramadol during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if
not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is
required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and
ensure that appropriate treatment will be available.
Interactions with drugs affecting cytochrome P450 isoenzymes:
The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol
are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol requires careful consideration of
the effects on the parent drug, tramadol, and the active metabolite, M1.
Risks from concomitant use with benzodiazepines or other CNS depressants:
Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation,
respiratory depression, coma, and death. Reserve concomitant prescribing of tramadol and benzodiazepines or other CNS
depressants for use in patients for whom alternative treatment options are inadequate. Limit treatment to the minimum effective
dosages and durations. Follow patients for signs and symptoms of respiratory depression and sedation.
Brand Names: US
ConZip;
Qdolo;
Ultram [DSC]
Brand Names: Canada

APO-Tramadol;
AURO-Tramadol;
Durela;
JAMP Tramadol;
MAR-Tramadol;
Ralivia;
SANDOZ Tramadol [DSC];
TARO-Tramadol ER;
Tridural;
Ultram [DSC];
Zytram XL
Pharmacologic Category
Analgesic, Opioid
Dosing: Adult
Collapse All
Pain management, moderate to severe 
Pain management, moderate to severe:
Note: In general, opioids may be considered a potential component of a comprehensive, multimodal, patient-specific
treatment plan for pain. Nonopioid analgesia should be maximized, if appropriate, prior to initiation of opioid analgesia;
combination therapy with analgesics with differing mechanisms of action may improve efficacy and reduce the doses and/or
frequency required for each agent (Ref). Tramadol doses should be titrated to appropriate analgesic effect; use the lowest
effective dose for the shortest period of time. Tramadol is used for a variety of moderate to moderately severe painful
conditions and may be of particular benefit for patients with mixed nociceptive and neuropathic pain due to its dual
mechanism of action (Ref).
Acute pain (eg, postoperative):
Note: In patients who are experiencing acute pain severe enough to require opioids (in addition to appropriate
nonopioid analgesia), limit the quantity prescribed to the expected duration of acute pain; a quantity sufficient for ≤3
days is often adequate, whereas >7 days is rarely needed (Ref). Long-acting preparations are not recommended for
treatment of acute pain in opioid-naive patients (Ref). Some experts avoid the use of tramadol in patients with moderate
to severe acute pain due to the wide interpatient variability in metabolism and related incidences of adverse events and
unreliable analgesia (Ref).
Immediate release: Oral: Initial: 50 mg every 4 to 6 hours as needed (Ref); some experts suggest that 25 to 50 mg 3 times
per day may be sufficient for patients with moderate acute pain (Ref). The dose may be increased as needed and
tolerated to 50 to 100 mg every 4 to 6 hours (maximum: 400 mg/day) (Ref).
Chronic pain (alternative agent):
Note: Opioids, including tramadol, are not the preferred therapy for chronic noncancer pain due to insufficient evidence
of benefit and risk of serious harm; nonpharmacologic treatment and nonopioid analgesics are preferred with the
exception of pain from sickle cell disease and in end-of-life care (Ref). Opioids, including tramadol, should only be
considered in patients who experience clinically meaningful improvement in pain and function that outweighs patient
safety risks (Ref). The utility of tramadol in patients with chronic pain due to cancer is questionable, especially considering
its dual mechanism of action and dose ceiling (Ref).
Opioid-naive patients not currently on tramadol immediate release:
Immediate release: Oral: The ideal dosing regimen has not been established; consider restricting the initial dose to
<300 mg tramadol per day (ie, <50 mg morphine equivalents daily) (Ref). An example initial dose is 25 to 50 mg every 6
hours as needed (Rosenquist 2022). The dose may be increased as needed and tolerated to 50 to 100 mg every 4 to 6
hours (maximum: 400 mg/day) (Ref).
Extended release:
Note: Although manufacturer's labeling contains the following directions for initiating ER tramadol products in
opioid-naive patients with chronic pain, it is recommended that when starting opioid therapy, treatment be initiated
with an IR preparation to more accurately determine the daily opioid requirement and decrease the risk of overdose
(Ref). The CDC recommends that ER opioids be reserved for patients who have received IR opioids daily for ≥1 week
yet continue to experience severe, continuous pain (Ref).
Initial: Oral: 100 mg once daily; titrate by 100 mg/day increments every 5 days as needed (maximum: 300
mg/day)
Tridural [Canadian product]: Initial: Oral: 100 mg once daily; titrate by 100 mg/day increments every 2 days as
needed (maximum: 300 mg/day)
Zytram XL [Canadian product]: Oral: 150 mg once daily; if pain relief is not achieved, may titrate by increasing
dosage incrementally with sufficient time to evaluate effect of increased dosage, generally not more often than
every 7 days (maximum: 400 mg/day).
Patients currently on tramadol IR tablets for ≥1 week: Calculate 24-hour tramadol IR tablet total dose and initiate total ER
daily dose (round dose to the next lowest 100 mg increment); titrate as needed and tolerated to desired effect (maximum:
300 mg/day). In patients who experience breakthrough pain, clinicians may consider the addition of an IR rescue
analgesic (eg, NSAID or short-acting weak opioid). Note: Oral solution relative bioavailability compared to ER products
has not been established; conversion to ER products should be accompanied by close monitoring of excessive sedation
and respiratory depression.
Discontinuation or tapering of therapy: When discontinuing or tapering chronic opioid therapy, the dose should be gradually
tapered down. An optimal universal tapering schedule for all patients has not been established (Ref). Proposed schedules
range from slow (eg, 10% reductions per week or 10% reduction per month depending on duration of chronic therapy) to
rapid (eg, 25% to 50% reduction every few days) (Ref). Individualize based on discussions with patient to minimize opioid
withdrawal while considering patient-specific goals and concerns as well as the pharmacokinetics of the opioid being tapered.
Slower tapers may be appropriate in patients who have been receiving opioids for a long duration (eg, years), particularly in
the final stage of tapering, whereas more rapid tapers may be appropriate in patients experiencing severe adverse events
(Ref). Monitor carefully for signs/symptoms of withdrawal. If the patient displays withdrawal symptoms, consider slowing the
taper schedule; alterations may include increasing the interval between dose reductions, decreasing amount of daily dose
reduction, pausing the taper and restarting when the patient is ready, and/or coadministration of an alpha-2 agonist (eg,
clonidine) to blunt withdrawal symptoms (Ref). Continue to offer nonopioid analgesics as needed for pain management
during the taper; consider nonopioid adjunctive treatments for withdrawal symptoms (eg, GI complaints, muscle spasm) as
needed (Ref).
Premature ejaculation 
Premature ejaculation (alternative agent) (off-label use):
Note: Tramadol may be considered in patients who have failed other therapies (eg, SSRIs, topical anesthetics). Consideration
should be given to the risk of addiction and adverse effects associated with opioids (Ref); to promote safe use, regular follow-
up to monitor for response, toxicity, and misuse is recommended.
Immediate release: Oral: The ideal dosing regimen has not been established; dosage range studied: 25 to 50 mg administered
on demand 1 to 3 hours prior to intercourse (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or
avoidance. Consult drug interactions database for more information.
Dosing: Kidney Impairment: Adult
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce
Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function (Ref):
CrCl ≥30 mL/minute: Immediate release, extended release: No dosage adjustment necessary.
CrCl <30 mL/minute: Immediate release: Increase dosing interval to every 12 hours; maximum: 200 mg/day. ER formulation
should be avoided.
Hemodialysis, intermittent (thrice weekly): Dialyzable (7%):
Immediate release: Lower initial doses and an extended dosing interval (eg, 25 mg twice daily) are recommended (Ref); titrate to
response. The manufacturer’s labeling recommends a maximum daily dose of 200 mg/day; however, since a uremic state may
lower seizure threshold, some experts recommend not exceeding 50 mg twice daily (Ref). ER formulation should be avoided.
Peritoneal dialysis: Dialyzability unknown (Davison 2014):
Immediate release: Lower initial doses and an extended dosing interval (eg, 25 mg twice daily) are recommended (Ref); titrate to
response. Although a maximum daily dose of 200 mg/day has been suggested (Ref), some experts recommend not exceeding
100 mg/day since a uremic state may lower the seizure threshold (Ref). ER formulation should be avoided.
Dosing: Hepatic Impairment: Adult
Immediate release:
Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling.
Severe impairment: 50 mg every 12 hours.
Extended release:
Mild to moderate impairment (Child-Pugh class A and B): There are no dosage adjustments provided in the manufacturer’s
labeling; use with caution.
Severe impairment (Child-Pugh class C): Avoid use.
Dosing: Pediatric
(For additional information see "Tramadol: Pediatric drug information")

Note: Doses should be titrated to appropriate analgesic effect; use the lowest effective dose for the shortest period of time:
Pain management, moderate to severe pain (excluding postoperative tonsillectomy/adenoidectomy pain): Note: The FDA has
recommended that tramadol not be used in pediatric patients <12 years of age and all pediatric patients undergoing tonsillectomy
and/or adenoidectomy due to increased risk of breathing problems (sometimes fatal). Slowed or difficult breathing has been
reported in pediatric patients <18 years of age; risk may be increased in pediatric patients who are obese or have conditions such as
obstructive sleep apnea or severe lung disease, or who are ultrarapid metabolizers of the drug (Ref).
Acute pain: Immediate-release formulations:
Children and Adolescents 4 to ≤16 years: Limited data available: Oral: 1 to 2 mg/kg/dose every 4 to 6 hours; maximum
single dose: 100 mg (usual adult starting dose: 50 to 100 mg); maximum daily dose is the lesser of 8 mg/kg/day or 400
mg/day (Ref). Note: Due to potential respiratory complications, tramadol should be avoided in patients <12 years of age
and all pediatric patients undergoing tonsillectomy and/or adenoidectomy (Ref).
Adolescents ≥17 years: Oral: 50 to 100 mg every 4 to 6 hours; maximum daily dose: 400 mg/day. For patients not requiring
rapid onset of effect, tolerability to adverse effects may be improved by initiating therapy at 25 mg/day and titrating dose by
25 mg every 3 days until 25 mg 4 times daily is reached. Dose may then be increased by 50 mg every 3 days as tolerated to
reach 50 mg 4 times daily.
Chronic pain: Extended-release formulations: Adolescents ≥18 years: Oral: Note: For patients requiring around-the-clock pain
management for an extended period of time. Opioids, including tramadol, are not the preferred therapy for chronic noncancer
pain due to insufficient evidence of benefit and risk of serious harm; nonpharmacologic treatment and nonopioid analgesics are
preferred with the exception of pain from sickle cell disease and in end-of-life care (Ref). Opioids, including tramadol, should
only be considered in patients who experience clinically meaningful improvement in pain and function that outweighs patient
safety risks (Ref).
Patients not currently on immediate-release tramadol: 100 mg once daily; titrate every 5 days; maximum daily dose: 300
mg/day.
Patients currently on immediate-release tramadol: Calculate 24-hour total immediate-release tramadol dose and initiate
total extended-release daily dose (round dose to the next lowest 100 mg increment) once daily; titrate as tolerated to
desired effect; maximum daily dose: 300 mg/day.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or
avoidance. Consult drug interactions database for more information.
Dosing: Kidney Impairment: Pediatric
Immediate release: Adolescents ≥17 years:
CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
CrCl <30 mL/minute: Increase dosing interval to every 12 hours; maximum daily dose: 200 mg/day.
Dialysis: Dialyzable (7%); increase dosing interval to every 12 hours; maximum daily dose: 200 mg/day; administer regular dose
on the day of dialysis.
Extended release: Adolescents ≥18 years:
CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
CrCl <30 mL/minute: Avoid use.
Dosing: Hepatic Impairment: Pediatric
Immediate release: Adolescents ≥17 years: There are no dosage adjustments provided in the manufacturer's labeling. In patients
with cirrhosis, recommended dose is 50 mg every 12 hours.
Extended release: Adolescents ≥18 years:
Mild to moderate impairment (Child-Pugh class A and B): There are no dosage adjustments provided in the manufacturer's
labeling; use with caution.
Severe impairment (Child-Pugh class C): Avoid use.
Dosing: Older Adult

Elderly >65 years to ≤75 years: Refer to adult dosing; use with caution and initiate at the low end of the dosing range.
Elderly >75 years:
Immediate release: Maximum: 300 mg/day.
Extended release: Use with extreme caution.
Dosage Forms: US
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] =
Discontinued product
Capsule Extended Release 24 Hour, Oral, as hydrochloride:
ConZip: 100 mg, 200 mg, 300 mg [contains fd&c blue #2(indig carmine)aluminum lake, quinoline (d&c yellow #10) aluminum
lake]
Generic: 100 mg, 150 mg [DSC], 200 mg, 300 mg
Solution, Oral, as hydrochloride:
Qdolo: 5 mg/mL (473 mL) [contains propylene glycol, sodium benzoate; grape flavor]
Generic: 5 mg/mL (5 mL)
Tablet, Oral, as hydrochloride:
Ultram: 50 mg [DSC] [scored; contains corn starch]
Generic: 50 mg, 100 mg
Tablet Extended Release 24 Hour, Oral, as hydrochloride:
Generic: 100 mg, 200 mg, 300 mg
Generic Equivalent Available: US

Yes
Dosage Forms Considerations

ConZip extended release capsules are formulated as a biphasic product, providing immediate and extended release components:
100 mg: 25 mg (immediate release) and 75 mg (extended release)
EnovaRX-Tramadol and Active-Tramadol creams are compounded from kits. Refer to manufacturer’s labeling for compounding
instructions.
Synapryn FusePaq is a compounding kit for the preparation of an oral suspension. Refer to manufacturer's labeling for
compounding instructions.
Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] =
Discontinued product
Capsule Extended Release 24 Hour, Oral, as hydrochloride:
Durela: 100 mg, 200 mg, 300 mg [contains fd&c blue #2(indig carmine)aluminum lake, quinoline (d&c yellow #10) aluminum
lake]
Tablet, Oral, as hydrochloride:
Ultram: 50 mg [DSC]
Generic: 50 mg
Tablet Extended Release 24 Hour, Oral:
Zytram XL: 75 mg [contains fd&c blue #2 (indigo carmine,indigotine)]
Zytram XL: 150 mg, 400 mg
Tablet Extended Release 24 Hour, Oral, as hydrochloride:
Ralivia: 100 mg, 200 mg, 300 mg
Tridural: 100 mg, 200 mg, 300 mg
Zytram XL: 100 mg, 200 mg, 300 mg
Generic: 100 mg, 200 mg, 300 mg
Controlled Substance
C-IV
Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this
medication:
ConZip: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022370s020lbl.pdf#page=35
Qdolo: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214044s000lbl.pdf#page=27
Ultram: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020281s048lbl.pdf#page=42
Ultram ER: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021692s015lbl.pdf#page=36
Administration: Adult
Oral:
Immediate release: Administer without regard to meals. Measure oral solution with a calibrated oral syringe or other oral dosing
device with metric units of measure (do not use household teaspoons or tablespoons); ensure accurate dosing between mg and mL.
Extended release: Swallow whole; do not crush, chew, dissolve, or split.
Capsule: Administer without regard to meals.
Tablet: Administer without regard to meals but administer in a consistent manner of either with or without meals.
Canadian products:
Durela, Ralivia, Zytram XL: Administer without regard to meals.
Tridural: Administer once daily with breakfast.

Bariatric surgery:
Capsule and tablet, extended release: Some institutions may have specific protocols that conflict with these
recommendations; refer to institutional protocols as appropriate. ER capsule should be swallowed whole. Do not crush,
chew, dissolve, or split as this may result in rapid release and a potentially fatal dose of tramadol. IR tablet formulation is
available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after
bariatric surgery; however, clinicians are advised to monitor closely for adverse effects and withdrawal symptoms after
bariatric surgery. Oral morphine has been shown to have significantly increased Cmax and decreased Tmax in the immediate
period (1 to 2 weeks) and long-term (6 months) period after bariatric surgery.
Administration: Pediatric
Oral:
Immediate-release tablet: May administer with or without food, but it is recommended that it be administered in a consistent
manner.
Extended-release tablet: Swallow whole with a sufficient amount of liquid. Do not crush, cut, dissolve, or chew extended-release
tablet; may be taken without regard to meals; tablet should be taken once daily at approximately the same time each day.
Use: Labeled Indications
Pain management:
Extended release: Management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for
which alternative treatment options are inadequate.
Immediate release: Management of pain severe enough to require an opioid analgesic and for which alternative treatments are
inadequate.
Limitations of use: Reserve tramadol for use in patients for whom alternative treatment options (eg, nonopioid analgesics) are
ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Tramadol ER is not indicated
as an as-needed analgesic.
Use: Off-Label: Adult
Premature ejaculation
Medication Safety Issues

Sound-alike/look-alike issues:
TraMADol may be confused with tapentadol, Toradol Trandate, traZODone, Voltaren
Ryzolt may be confused with Rydapt
Ultram may be confused with lithium, Ultane, Ultracet, Voltaren
High alert medication:
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a
heightened risk of causing significant harm when used in error.
Older Adult: High-Risk Medication:
Beers Criteria: Tramadol is identified in the Beers Criteria as a potentially inappropriate medication to be used with caution in
patients 65 years and older due to the potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone
secretion (SIADH) or hyponatremia; monitor sodium concentration closely when initiating or adjusting the dose in older adults
(Beers Criteria [AGS 2019]).
Pediatric patients: High-risk medication:
KIDs List: Tramadol, when used in pediatric patients <18 years of age, is identified on the Key Potentially Inappropriate Drugs in
Pediatrics (KIDs) list and should be used with caution due to risk of respiratory depression unless pharmacogenetic testing
completed (weak recommendation; low quality of evidence) (PPA [Meyers 2020]).
International issues:
Theradol [Netherlands] may be confused with Foradil brand name for formoterol [US, Canada, and multiple international
markets], Terazol brand name for terconazole [US and Canada], and Toradol brand name for ketorolac [Canada and multiple
international markets]
Trexol [Mexico] may be confused with Trexall brand name for methotrexate [US]; Truxal brand name for chlorprothixene
[multiple international markets]
Adverse Reactions (Significant): Considerations

CNS effects
Various CNS effects have been reported in association with tramadol use in clinical trials and case reports. In clinical trials, the most
common CNS effects include dizziness, sedated state, drowsiness, headache, and central nervous system stimulation. Less
commonly reported CNS adverse effects include euphoria, anxiety, depression, anger, hostility, aggression, lack of
concentration, and cognitive dysfunction (Ref). In contrast, improvements in anxiety and depression symptoms have been
reported during tramadol use (Ref). Euphoric effects and possible antianxiety and antidepressant effects may contribute to the
addiction potential of tramadol (Ref).
Mechanism: Dose-related; tramadol metabolism to active metabolite, M1, may contribute to euphoric effect (Ref).
Risk factors:
• Dose; generally greater with higher doses
• Concurrent use of CNS depressant medications
• CYP2D6 ultra-rapid metabolizers
Constipation
Constipation has been reported in patients taking opioids, including tramadol (Ref).
Mechanism: Dose-related; related to the pharmacologic action (ie, activation of mu opioid receptors in the GI tract resulting in
decreased peristalsis, reduced mucosal secretions, and delayed gastric emptying) (Ref).
Onset: Intermediate; occurs within first 4 weeks of therapy (Ref). Minimal to no tolerance to constipation develops with chronic
use ((Ref).
Risk factors:
• Dose; generally greater with higher doses
Hyponatremia
Hyponatremia has been reported with tramadol use; many cases have been severe (sodium <120 mmol/L). Some cases have
occurred due to the syndrome of inappropriate antidiuretic hormone.
Onset: Varied; most cases have occurred within the first week of initiation.
Risk factors:
• Females >65 years of age may be at higher risk
Respiratory depression
Life-threatening or fatal respiratory depression has occurred with opioids, including tramadol, at therapeutic and supratherapeutic
doses in adult and pediatric patients (Ref). Respiratory depression may be reversible with medical intervention (Ref). Tramadol may
be associated with less risk of respiratory depression than other opioids in adults (Ref); in pediatric patients, a serious (sometimes
fatal) risk of respiratory depression exists with tramadol and is similar to that of opioids such as codeine (Ref).
Mechanism: Dose-related; related to the pharmacologic action (ie, activation of mu opioid receptors in the CNS respiratory
center) (Ref).
Onset: Rapid; mean of 8 hours after ingestion (range: 1 to 24 hours); dependent on dose and patient variables (eg, CYP2D6 ultra-
rapid metabolizer, kidney impairment) (Ref).
Risk factors:
• Dose; generally greater with higher doses (Ref)
• Age ≥65 years (Ref)
• Cachexia
• Cardiovascular disease (Ref)
• Chronic pulmonary disease (Ref)
• Concurrent use of other psychoactive medications (eg, benzodiazepines or CNS depressants, antipsychotics) (Ref)
• CYP2D6 ultra-rapid metabolizers (adult and pediatric) (Ref)
• Debilitation
• Depression (or other concurrent psychiatric illness) (Ref)
• Kidney or liver impairment (Ref)
• Substance use disorder (Ref)
• Pediatric:
• Age <12 years of age (Ref)
• Age ≥12 years with comorbid conditions like obesity, obstructive sleep apnea, or severe lung disease, which may
increase the risk of serious breathing problem (Ref)
Seizures
Seizure has been reported after therapeutic and supratherapeutic doses of tramadol (Ref). Seizures typically present as a single
generalized tonic-clonic episode lasting <5 minutes (Ref); although, recurrent seizures have been reported (Ref).
Mechanism: Dose-related. Mechanism not fully elucidated; may be related to excessive serotonergic activity (Ref), opioid-
dependent GABA receptor inhibition (Ref), and/or opioid-receptor dependent histamine release (Ref).
Onset: Rapid; occurs within 4 to 6 hours of ingestion (Ref).
Risk factors:
• Dose; generally greater with higher doses (Ref)
• Concurrent medications: Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors
(SNRIs), tricyclic antidepressants (TCAs) and other tricyclic compounds (eg, cyclobenzaprine, promethazine), other opioids,
monoamine oxidase inhibitors (MAOIs), anorectics, neuroleptics, drugs that reduce the seizure threshold, and/or drugs that
impair metabolism of tramadol (eg, CYP2D6 and 3A4 inhibitors)
• CYP2D6 poor metabolizers (Ref)
• History of seizure disorder
• Patients otherwise at risk for seizures (ie, alcohol withdrawal, CNS infections, head trauma)
Serotonin syndrome
Life-threatening serotonin syndrome has been reported after therapeutic and supratherapeutic doses of tramadol (Ref). Risk is
increased when tramadol is administered in combination with agents that increase its plasma concentrations (eg, CYP2D6 and
CYP3A4 inhibitors) and with other serotonergic agents. However, it has been reported after tramadol monotherapy; more often
observed in the setting of overdose (Ref). Serotonin syndrome may be reversible with medical intervention (Ref).
Mechanism: Excessive serotonin concentrations at the synaptic cleft and/or inhibition of tramadol metabolism leading to
increased tramadol concentrations (Ref).
Onset: Varied; may occur within several hours to days after administration or may present later.
Risk factors:
• Concurrent use of serotonergic medications: Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine
reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), triptans, etc. (Ref)
• Concurrent use of CYP2D6 and/or CYP3A4 inhibitors (Ref)
• CYP2D6 poor metabolizers (Ref)
• Age >65 years (Ref)
Withdrawal syndrome
Physical dependence, manifesting as a withdrawal syndrome, has been observed after abrupt discontinuation of tramadol (Ref).
Reported symptoms are consistent with both opioid and serotonin withdrawal (Ref). Withdrawal symptoms may occur after several
days or longer therapy durations. Withdrawal symptoms usually resolve within 2 to 7 days (Ref).
Mechanism: Withdrawal; autonomic hyperexcitability in the absence of opioid agonist suppressive effects (Ref); reduced
availability of serotonin (Ref).
Onset: Rapid; symptom onset typically occurs within 24 hours of discontinuing tramadol therapy and usually resolves within 2 to
7 days (Ref).
Risk factors:
• Abrupt discontinuation of tramadol in physically dependent patients
• Concurrent use of opioid mixed agonist/antagonists, opioid partial agonists, or naloxone (Ref)
• Duration of use (potential risk factor) (Ref)
• Higher doses (Ref)
Adverse Reactions
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Gastrointestinal: Constipation (9% to 21%; placebo: 4%), dyspepsia, nausea (15% to 26%), xerostomia (5% to 13%)
Nervous system: Dizziness (10% to 23%; placebo: 5% to 7%), drowsiness (7% to 16%; placebo: 2% to 4%), headache (12% to 23%;
placebo: 11% to 20%), vertigo
1% to 10%:
Cardiovascular: Chest pain (1% to <5%), flushing (8% to 10%), hypertension (1% to <5%), orthostatic hypotension (≤4%),
peripheral edema (<5%), vasodilation (1% to <5%)
Dermatologic: Dermatitis (1% to <5%), diaphoresis (2% to 7%), pruritus (3% to 9%), skin rash (1% to <5%)
Endocrine & metabolic: Hot flash (1% to <5%), hyperglycemia (1% to <5%), weight loss (1% to <5%)
Gastrointestinal: Abdominal pain (1% to <5%; upper abdominal pain: 1% to <5%), anorexia (1% to 6%), decreased appetite (1% to
<5%), diarrhea (7% to 9%), flatulence (<5%), vomiting (5% to 10%)
Genitourinary: Menopausal symptoms (1% to <5%), pelvic pain (1% to <5%), prostatic disease (1% to <5%), urinary frequency
(<5%), urinary retention (<5%), urinary tract infection (1% to <5%)
Nervous system: Agitation (<5%), anxiety (1% to <5%), apathy (1% to <5%), ataxia (1% to <5%), chills (1% to <5%), confusion (1%
to <5%), depersonalization (1% to <5%), depression (1% to <5%), euphoria (<5%), falling (1% to <5%), hypertonia (<5%),
hypoesthesia (1% to <5%), insomnia (5% to 9%), lethargy (1% to <5%), malaise (<5%), nervousness (1% to <5%), paresthesia (1%
to <5%), restlessness (1% to <5%), rigors (1% to <5%), sleep disorder (<5%), withdrawal syndrome (<5%)
Neuromuscular & skeletal: Arthralgia (1% to <5%), asthenia (4% to 9%), back pain (1% to <5%), increased creatine phosphokinase
in blood specimen (1% to <5%), limb pain (1% to <5%), myalgia (<5%), neck pain (1% to <5%), tremor (<5%)
Ophthalmic: Blurred vision (1% to <5%), miosis (1% to <5%)
Respiratory: Bronchitis (1% to <5%), cough (1% to <5%), dyspnea (1% to <5%), flu-like symptoms (1% to <5%), nasal congestion
(1% to <5%), nasopharyngitis (1% to <5%), pharyngitis (1% to <5%), rhinitis (1% to <5%), rhinorrhea (1% to <5%), sinusitis (1% to
<5%), sneezing (1% to <5%), upper respiratory tract infection (1% to <5%)
Miscellaneous: Accidental injury (<5%), fever (1% to <5%)
<1%:
Cardiovascular: Acute myocardial infarction, hypotension, ischemic heart disease, lower extremity edema, palpitations,
peripheral ischemia, syncope, tachycardia
Dermatologic: Cellulitis, cold and clammy skin, ecchymoses, night sweats, piloerection, skin vesicle, Stevens-Johnson syndrome
(Mockenhaupt 2008), toxic epidermal necrolysis (Mockenhaupt 2008), urticaria
Endocrine & metabolic: Decreased libido, gout, increased gamma-glutamyl transferase, menstrual disease
Gastrointestinal: Appendicitis, cholecystitis, cholelithiasis, dysgeusia, gastroenteritis, pancreatitis
Genitourinary: Cystitis, dysuria, hematuria
Hematologic & oncologic: Anemia, bruise
Nervous system: Abnormal dreams, cognitive dysfunction, disorientation, emotional lability, hallucination, irritability, lack of
concentration, migraine, sedated state, seizure (Memarian 2018), serotonin syndrome (Shakoor 2014), suicidal tendencies,
yawning
Neuromuscular & skeletal: Hyperkinetic muscle activity, joint stiffness, lower limb cramp, muscle cramps, muscle spasm, muscle
twitching, neck stiffness
Otic: Otitis, tinnitus
Respiratory: Pneumonia
Frequency not defined:
Hypersensitivity: Angioedema
Neuromuscular & skeletal: Muscle spasticity
Respiratory: Bronchospasm
Postmarketing:
Cardiovascular: Prolonged QT interval on ECG, pulmonary embolism, torsades de pointes
Dermatologic: Erythema multiforme (Sanchez-Gonzalez 2020)
Endocrine & metabolic: Adrenocortical insufficiency (Debono 2011), hypoglycemia (within 30 days of initiation [Fournier 2015,
Odonkor 2016]; may occur more often in patients with predisposing risk factors [eg, diabetes] and may result in hospitalization),
hyponatremia
Gastrointestinal: Gastrointestinal hemorrhage, stomatitis
Genitourinary: Proteinuria
Hepatic: Hepatic failure, hepatitis
Hypersensitivity: Anaphylaxis (<0.1%) (Mori 2015)

Nervous system: Delirium (Agrawal 2009, Kunig 2006)
Neuromuscular & skeletal: Femoral neck fracture (Wei 2020)
Ophthalmic: Cataract, mydriasis (Makris 2012)
Otic: Deafness
Respiratory: Pulmonary edema, respiratory depression (Hassanian-Moghaddam 2013)
Contraindications
Hypersensitivity (eg, anaphylaxis) to tramadol, opioids, or any component of the formulation; pediatric patients <12 years of age;
postoperative management in pediatric patients <18 years of age who have undergone tonsillectomy and/or adenoidectomy;
significant respiratory depression; acute or severe bronchial asthma in the absence of appropriately monitored settings and/or
resuscitative equipment; GI obstruction, including paralytic ileus (known or suspected); concomitant use with or within 14 days
following monoamine oxidase inhibitor therapy.
Canadian products: Additional contraindications (not in US labeling): (Note: Contraindications may differ between product labeling;
refer also to product labeling): Severe renal impairment (CrCl <30 mL/minute), severe hepatic impairment (Child-Pugh class C); mild,
intermittent, or short-duration pain that can be managed with other pain medication; management of perioperative pain; status
asthmaticus, chronic obstructive airway, acute respiratory depression, hypercapnia, cor pulmonale, delirium tremens, seizure
disorder, severe CNS depression, increased cerebrospinal or intracranial pressure, brain tumor, head injury, suspected surgical
abdomen (eg, acute appendicitis or pancreatitis); acute intoxication with ethanol, hypnotics, centrally acting analgesics, opioids, or
psychotropic drugs; breastfeeding, pregnancy; use during labor and delivery.
Warnings/Precautions
Concerns related to adverse effects:
• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with
hypovolemia, cardiovascular disease (including acute myocardial infarction [MI]), or drugs that may exaggerate hypotensive
effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose
titration. Avoid use in patients with circulatory shock.
Disease-related concerns:
• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term
opioid use may cause secondary hypogonadism, which may lead to mood disorders and osteoporosis (Brennan 2013).
• Biliary tract impairment: Use caution in patients with biliary tract dysfunction or acute pancreatitis; opioids may cause spasm
of the sphincter of Oddi.
• CNS depression/coma: Avoid use in patients with impaired consciousness or coma as these patients are susceptible to
intracranial effects of CO2 retention.
• Diabetes: Use with caution in patients with diabetes; tramadol may cause hypoglycemia.
• Delirium tremens: Use with caution in patients with delirium tremens.
• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP);
exaggerated elevation of ICP may occur.
• Hepatic impairment: Use with caution; dosage adjustments may be required. ER formulations should not be used in severe
hepatic impairment (Child-Pugh class C).
• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression,
anxiety disorders, post-traumatic stress disorder) due to increased risk for opioid use disorder and overdose; more frequent
monitoring is recommended (CDC [Dowell 2016]).
• Obesity: Use with caution in patients who are morbidly obese.
• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.
• Psychosis: Use with caution in patients with toxic psychosis.
• Renal impairment: Use with caution; reduce dosage of IR formulations in patients with severe renal impairment; ER
formulations should be avoided in severe renal impairment.
• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive
pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or
preexisting respiratory depression, particularly when initiating and titrating therapy; critical respiratory depression may occur,
even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.
• Sleep-related disorders: Opioid use increases the risk for sleep-related disorders (eg, central sleep apnea [CSA], hypoxemia) in
a dose-dependent fashion. Use with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-
disordered breathing (eg, heart failure, obesity). Consider dose reduction in patients presenting with CSA. Avoid opioids in
patients with moderate to severe sleep-disordered breathing (CDC [Dowell 2016]).
• Suicide risk: Avoid use in patients who are suicidal; use with caution in patients taking tranquilizers and/or antidepressants, or
those with an emotional disturbance including depression. Consider the use of alternative nonopioid analgesics in these
patients.
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.
Special populations:
• CYP2D6 "poor metabolizers": Poor metabolizers have decreased metabolism of tramadol to its active metabolite, which may
diminish analgesia; avoid the use of tramadol and consider alternatives that are not metabolized by CYP2D6 (CPIC [Crews
2021]).
• CYP2D6 "ultrarapid metabolizers": Ultrarapid metabolizers have increased metabolism of tramadol to its active metabolite,
which may increase the risk of toxicity; avoid the use of tramadol and consider alternatives that are not metabolized by CYP2D6
(CPIC [Crews 2021]). The occurrence of this phenotype is seen in ~1% to 2% of East Asian patients (Chinese, Japanese, Korean),
1% to 10% of Caucasian patients, 3% to 4% of Black patients, and may be >10% in certain racial/ethnic groups (ie, Oceanian,
Northern African, Middle Eastern, Ashkenazi Jewish, and Puerto Rican patients). Deaths have also occurred in breastfeeding
infants after being exposed to high concentrations of morphine because the mothers were ultrarapid metabolizers of codeine.
• Older adult: Use opioids for chronic pain with caution in older adults; monitor closely due to an increased potential for risks,
including certain risks such as falls/fracture, cognitive impairment, and constipation. Clearance may also be reduced in older
adults (with or without renal impairment) resulting in a narrow therapeutic window and increasing the risk for respiratory
depression or overdose (CDC [Dowell 2016]). Consider the use of alternative nonopioid analgesics in these patients.
• Pediatric: Respiratory depression:Risk factors include conditions associated with hypoventilation, such as postoperative status,
obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications
that cause respiratory depression.
Other warnings/precautions:
• Abuse/misuse/diversion: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug
dependency exists. Other risk factors associated with increased risk include a personal or family history of substance use
disorder or mental illness (eg, major depression).
• Appropriate use: Chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or
medication-based opioid use disorder treatment) in outpatient setting in adults: Opioids should not be used as first-line therapy
for chronic pain management (pain >3-month duration or beyond time of normal tissue healing) due to limited short-term
benefits, undetermined long-term benefits, and association with serious risks (eg, overdose, MI, auto accidents, risk of
developing opioid use disorder). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg,
nonsteroidal anti-inflammatory drugs, acetaminophen, certain antiseizure and antidepressant medications). If opioid therapy is
initiated, it should be combined with nonpharmacologic and nonopioid therapy, as appropriate. Prior to initiation, known risks
of opioid therapy should be discussed and realistic treatment goals for pain/function should be established, including
consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued only if clinically meaningful
improvement in pain/function outweighs risks. Therapy should be initiated at the lowest effective dosage using IR opioids
(instead of ER/long-acting opioids). Risk associated with use increases with higher opioid dosages. Risks and benefits should be
re-evaluated when increasing dosage to ≥50 MME/day orally; dosages ≥90 MME/day orally should be avoided unless carefully
justified (CDC [Dowell 2016]).
• Naloxone access: Discuss the availability of naloxone with all patients who are prescribed opioid analgesics, as well as their
caregivers, and consider prescribing it to patients who are at increased risk of opioid overdose. These include patients who are
also taking benzodiazepines or other CNS depressants, have an opioid use disorder (OUD) (current or history of), have
experienced a previous opioid overdose, have a history of a substance use disorder, or have higher opioid dosages (≥50
morphine milligram equivalents [MME]/day orally) (CDC [Dowell 2016]). Additionally, health care providers should consider
prescribing naloxone to patients prescribed medications to treat OUD; patients at risk of opioid overdose even if they are not
taking an opioid analgesic or medication to treat OUD; and patients taking opioids, including methadone or buprenorphine for
OUD, if they have household members, including children, or other close contacts at risk for accidental ingestion or opioid
overdose. Inform patients and caregivers on options for obtaining naloxone (eg, by prescription, directly from a pharmacist, a
community-based program) as permitted by state dispensing and prescribing guidelines. Educate patients and caregivers on
how to recognize respiratory depression, proper administration of naloxone, and getting emergency help.
• Optimal regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type
of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic
user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to
pain relief/prevention.
• Surgery: Opioids decrease bowel motility; monitor for decrease bowel motility in postop patients receiving opioids. Use with
caution in the perioperative setting; individualize treatment when transitioning from parenteral to oral analgesics.
Warnings: Additional Pediatric Considerations
In April 2017, the FDA announced tramadol use should be avoided in all pediatric patients <12 years and all pediatric patients
undergoing tonsillectomy or adenoidectomy. The FDA is requiring updated manufacturer labeling to include in the following
contraindications: Use in patients <12 years to treat pain and use in patients <18 years to treat postoperative
tonsillectomy/adenoidectomy pain (FDA 2017).
Metabolism/Transport Effects
Substrate of CYP2B6 (minor), CYP2D6 (major), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically
relevant drug interaction potential
Drug Interactions
(For additional information: Launch drug interactions program)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4
Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management
recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Almotriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome.
Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia,
diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Alvimopan: Opioid Agonists may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-
term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving
therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy
modification
Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating
effect of Amifampridine. Risk C: Monitor therapy
Amphetamines: May enhance the analgesic effect of Opioid Agonists. Risk C: Monitor therapy
Amphetamines: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome.
diaphoresis, tremor, autonomic instability). Initiate amphetamines at lower doses, monitor frequently, and adjust doses as needed.
Risk C: Monitor therapy
Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary
retention may be increased with this combination. Risk C: Monitor therapy
Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of TraMADol. Management: Monitor for signs and symptoms
of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental
status changes) when these agents are combined. Risk C: Monitor therapy
Artemether and Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C:
Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering
blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not
be coadministered with blonanserin. Risk D: Consider therapy modification
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
BuPROPion: May enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering
Potential. Risk C: Monitor therapy
BusPIRone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome.
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products.
Risk C: Monitor therapy
CarBAMazepine: TraMADol may enhance the CNS depressant effect of CarBAMazepine. TraMADol may diminish the therapeutic
effect of CarBAMazepine. CarBAMazepine may decrease the serum concentration of TraMADol. Risk X: Avoid combination
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of
excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a
combination must be used. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CNS Depressants: May enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid
agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative
treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
CYP2D6 Inhibitors (Moderate): May decrease serum concentrations of the active metabolite(s) of TraMADol. CYP2D6 Inhibitors
(Moderate) may increase the serum concentration of TraMADol. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May decrease serum concentrations of the active metabolite(s) of TraMADol. CYP2D6 Inhibitors (Strong)
may increase the serum concentration of TraMADol. Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of TraMADol. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of TraMADol. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May increase serum concentrations of the active metabolite(s) of TraMADol. CYP3A4 Inhibitors
(Moderate) may increase the serum concentration of TraMADol. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of TraMADol. CYP3A4 Inhibitors (Strong)
may increase the serum concentration of TraMADol. Risk C: Monitor therapy
Dapoxetine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome.
Management: Do not use serotonergic agents (high risk) with dapoxetine or within 7 days of serotonergic agent discontinuation. Do
not use dapoxetine within 14 days of monoamine oxidase inhibitor use. Dapoxetine labeling lists this combination as
contraindicated. Risk X: Avoid combination
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or
any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant
with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Desmopressin: Opioid Agonists may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for
increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of
either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Dexmethylphenidate-Methylphenidate: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in
serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia,
clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C:
Monitor therapy
Dextromethorphan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin
syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus,
hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
therapy
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Digoxin: TraMADol may increase the serum concentration of Digoxin. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of
Diuretics. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of
other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
DULoxetine: May enhance the adverse/toxic effect of TraMADol. The risk for serotonin syndrome/serotonin toxicity and seizures may
be increased with this combination. DULoxetine may diminish the therapeutic effect of TraMADol. Management: Monitor for signs
and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic
instability, mental status changes), reduced tramadol effectiveness and seizures if these agents are combined. Risk C: Monitor therapy
Eletriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome.
Eluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination
Ergot Derivatives: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome.
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS
depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory
depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid
combination
Gastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk
C: Monitor therapy
Herbal Products with Glucose Lowering Effects: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C:
Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS
depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression
in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Risk C: Monitor
therapy
Iobenguane Radiopharmaceutical Products: TraMADol may diminish the therapeutic effect of Iobenguane Radiopharmaceutical
Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5
biological half-lives before iobenguane administration. Do not administer tramadol until at least 7 days after each iobenguane dose.
Risk X: Avoid combination
Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for
seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use
of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic
antiseizure drugs. Risk D: Consider therapy modification
Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk
for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal
use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of
prophylactic antiseizure drugs. Risk D: Consider therapy modification
Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the
risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to
intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider
use of prophylactic antiseizure drugs. Risk D: Consider therapy modification
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and
of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant
effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
Linezolid: May enhance the serotonergic effect of Serotonergic Opioids (High Risk). This could result in serotonin syndrome.
Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin
syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status
changes). Risk D: Consider therapy modification
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lorcaserin (Withdrawn From US Market): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in
serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia,
clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C:
Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may
enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting
methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D:
Consider therapy modification
Methylene Blue: May enhance the serotonergic effect of Serotonergic Opioids (High Risk). This could result in serotonin syndrome.
Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin
changes). Risk D: Consider therapy modification
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Metoclopramide: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome.
Management: Consider monitoring for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus,
therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors (Antidepressant): May enhance the adverse/toxic effect of TraMADol. Specifically, the risk for
serotonin syndrome/serotonin toxicity and seizures may be increased.. Risk X: Avoid combination
Monoamine Oxidase Inhibitors (Type B): Serotonergic Opioids (High Risk) may enhance the serotonergic effect of Monoamine
Oxidase Inhibitors (Type B). This could result in serotonin syndrome. Risk X: Avoid combination
Nalfurafine: Opioid Agonists may enhance the adverse/toxic effect of Nalfurafine. Opioid Agonists may diminish the therapeutic
effect of Nalfurafine. Risk C: Monitor therapy
Nalmefene: May diminish the therapeutic effect of Opioid Agonists. Management: Avoid the concomitant use of oral nalmefene and
opioid agonists. Discontinue oral nalmefene 1 week prior to any anticipated use of opioid agonists. If combined, larger doses of
opioid agonists will likely be required. Risk D: Consider therapy modification
Naltrexone: May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full
drug interaction monograph for detailed recommendations. Risk X: Avoid combination
Nefazodone: May enhance the adverse/toxic effect of TraMADol. Specifically, the risk for serotonin syndrome/serotonin toxicity and
seizures may be increased. Nefazodone may increase the serum concentration of TraMADol. Management: Monitor for signs and
symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic
instability, mental status changes), seizures, and tramadol adverse effects when these agents are combined. Risk C: Monitor therapy
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Ondansetron: May enhance the serotonergic effect of TraMADol. This could result in serotonin syndrome. Ondansetron may
diminish the therapeutic effect of TraMADol. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin
toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and diminished
tramadol efficacy when these agents are combined. Risk C: Monitor therapy
Opioids (Mixed Agonist / Antagonist): May diminish the analgesic effect of Opioid Agonists. Management: Seek alternatives to mixed
agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose
requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Risk X: Avoid combination
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxitriptan: Serotonergic Agents (High Risk) may enhance the serotonergic effect of Oxitriptan. This could result in serotonin
syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus,
therapy
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider
alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants
(including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D:
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of
oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative
treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Ozanimod: May enhance the adverse/toxic effect of Serotonergic Agents (High Risk). Risk C: Monitor therapy
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b
may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Pegvisomant: Opioid Agonists may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
PHENobarbital: May enhance the CNS depressant effect of TraMADol. PHENobarbital may decrease the serum concentration of
TraMADol. Management: Avoid use of tramadol and phenobarbital when possible. Monitor for respiratory depression/sedation.
Because phenobarbital is also a strong CYP3A4 inducer, monitor for decreased tramadol efficacy and withdrawal if combined. Risk D:
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Primidone: May enhance the CNS depressant effect of TraMADol. Primidone may decrease the serum concentration of TraMADol.
Management: Avoid use of tramadol and primidone when possible. Monitor for respiratory depression/sedation. Because primidone
is also a strong CYP3A4 inducer, monitor for decreased tramadol efficacy and withdrawal if combined. Risk D: Consider therapy
modification
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the
therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of
blood sugar control may occur with quinolone use. Risk C: Monitor therapy
Ramosetron: Opioid Agonists may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of
neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS
depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal
ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk
C: Monitor therapy
Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Samidorphan: May diminish the therapeutic effect of Opioid Agonists. Risk X: Avoid combination
Selective Serotonin Reuptake Inhibitors: TraMADol may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors.
Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased. Management: Monitor for signs and
instability, mental status changes) and seizures when these agents are combined. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors): May enhance the adverse/toxic effect of TraMADol. Specifically,
the risk for serotonin syndrome/serotonin toxicity and seizures may be increased. Selective Serotonin Reuptake Inhibitors (Strong
CYP2D6 Inhibitors) may diminish the therapeutic effect of TraMADol. Management: Monitor for signs and symptoms of serotonin
changes), seizures, and decreased tramadol efficacy when these agents are combined. Risk C: Monitor therapy
Serotonergic Agents (High Risk, Miscellaneous): Serotonergic Opioids (High Risk) may enhance the serotonergic effect of
Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and
instability, mental status changes) if these agents are combined. Risk C: Monitor therapy
Serotonergic Non-Opioid CNS Depressants: May enhance the CNS depressant effect of Serotonergic Opioids (High Risk).
Serotonergic Non-Opioid CNS Depressants may enhance the serotonergic effect of Serotonergic Opioids (High Risk). This could
result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and
symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk D: Consider therapy modification
Serotonergic Opioids (High Risk): May enhance the CNS depressant effect of TraMADol. Serotonergic Opioids (High Risk) may
enhance the serotonergic effect of TraMADol. This could result in serotonin syndrome. Management: Consider alternatives to this
drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk
D: Consider therapy modification
Serotonin 5-HT1D Receptor Agonists (Triptans): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could
result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg,
hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are
combined. Risk C: Monitor therapy
Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the adverse/toxic effect of TraMADol. Specifically, the risk for serotonin
syndrome/serotonin toxicity and seizures may be increased. Management: Monitor for signs and symptoms of serotonin
changes) and seizures when these agents are combined. Risk C: Monitor therapy
Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider
discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D:
Somatostatin Analogs: Opioid Agonists may diminish the analgesic effect of Somatostatin Analogs. Opioid Agonists may enhance
the analgesic effect of Somatostatin Analogs. Risk C: Monitor therapy
St John's Wort: May enhance the serotonergic effect of TraMADol. This could result in serotonin syndrome. St John's Wort may
decrease the serum concentration of TraMADol. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin
toxicity and reduced tramadol effects (including withdrawal symptoms) when combined. Monitor for increased tramadol effects if St
John's wort is discontinued. Risk C: Monitor therapy
Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. Risk C: Monitor therapy
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant
and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant
with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Syrian Rue: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome.
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Tricyclic Antidepressants: May enhance the CNS depressant effect of Serotonergic Opioids (High Risk). Serotonergic Opioids (High
Risk) may enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Management:
Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin
toxicity and CNS depression. Risk D: Consider therapy modification
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): TraMADol may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor
therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand
sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is
recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy
modification
Reproductive Considerations
Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction or infertility in men and women
(Brennan 2013).
Premature ejaculation may contribute to male infertility. Tramadol may be an alternative treatment for this condition; however, due to
the risk of addiction and adverse effects associated with opioid use, it should only be used in patients who have experienced treatment
failure with other therapies (ISSM [Althof 2014]; Martyn-St. James 2015).
Pregnancy Considerations
Tramadol crosses the placenta.
According to some studies, maternal use of opioids may be associated with birth defects (including neural tube defects, congenital heart
defects, and gastroschisis), poor fetal growth, stillbirth, and preterm delivery (CDC [Dowell 2016]).
[US Boxed Warning]: Prolonged use of tramadol during pregnancy can result in neonatal opioid withdrawal syndrome, which
may be life-threatening if not recognized and treated, and requires management according to protocols developed by
neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of
neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. If chronic opioid exposure occurs
in pregnancy, adverse events in the newborn (including withdrawal) may occur (Chou 2009). Symptoms of neonatal abstinence
syndrome (NAS) following opioid exposure may be autonomic (eg, fever, temperature instability), gastrointestinal (eg, diarrhea,
vomiting, poor feeding/weight gain), or neurologic (eg, high-pitched crying, hyperactivity, increased muscle tone, increased
wakefulness/abnormal sleep pattern, irritability, sneezing, seizure, tremor, yawning) (Dow 2012; Hudak 2012). Mothers who are
physically dependent on opioids may give birth to infants who are also physically dependent. Opioids may cause respiratory depression
and psycho-physiologic effects in the neonate; newborns of mothers receiving opioids during labor should be monitored.
Tramadol is not commonly used to treat pain during labor and immediately postpartum (ACOG 209 2019) or chronic noncancer pain in
pregnant women or those who may become pregnant (CDC [Dowell 2016]; Chou 2009).
Breastfeeding Considerations
Tramadol and the active M1 metabolite are present in breast milk. M1 has stronger opioid activity than tramadol. Actual exposure to
a breastfeeding infant may depend on the mothers CYP2D6 metabolism (Salman 2011).
Tramadol is not recommended for use in breastfeeding women. Due to the potential for serious adverse events in the breastfed
infant (including excess sedation and respiratory depression), use during breastfeeding is not recommended by the manufacturer.
Nonopioid analgesics are preferred for breastfeeding females who require pain control peripartum or for surgery outside of the
postpartum period (ABM [Martin 2018]; ABM [Reece-Stremtan 2017]). When opioids are needed in breastfeeding women, the lowest
effective dose for the shortest duration of time should be used to limit adverse events in the mother and breastfeeding infant. In
general, a single occasional dose of an opioid analgesic may be compatible with breastfeeding (WHO 2002). Breastfeeding women
using opioids for postpartum pain or for the treatment of chronic maternal pain should monitor their infants for drowsiness,
sedation, feeding difficulties, or limpness (ACOG 209 2019). Withdrawal symptoms may occur when maternal use is discontinued or
breastfeeding is stopped.
Monitoring Parameters
Pain relief, respiratory and mental status/alertness (especially in patients on concomitant CNS depressants, including
benzodiazepines), blood pressure, heart rate; blood glucose if hypoglycemia is suspected; signs/symptoms of hyponatremia (eg,
confusion, disorientation) especially during initiation of therapy; bowel function; signs/symptoms of tolerance, addiction, abuse,
misuse, or suicidal ideation; signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013); signs and symptoms of
serotonin syndrome such as mental status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia,
labile BP, hyperthermia), neuromuscular changes (eg, hyperreflexia, incoordination), and/or GI symptoms (eg, nausea, vomiting,
diarrhea); signs and symptoms of neonatal withdrawal syndrome in infants born to mothers using opioids during pregnancy (eg.
irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight); during
discontinuation of therapy monitor pain control, withdrawal symptoms, mood changes, suicidal ideation, and for use of other
substances.
Alternate recommendations: Chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle
cell disease, or medication-based opioid use disorder treatment): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of
treatment initiation and with dose increases. Re-evaluate benefits/risks every 3 months during therapy or more frequently in
patients at increased risk of overdose or opioid use disorder. Urine drug testing is recommended prior to initiation and re-checking
should be considered at least yearly (includes controlled prescription medications and illicit drugs of abuse). State prescription drug
monitoring program (PDMP) data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency
ranging from every prescription to every 3 months) (CDC [Dowell 2016]).
Reference Range
100 to 300 ng/mL; however, serum level monitoring is not required
Mechanism of Action
Tramadol and its active metabolite (M1) binds to μ-opiate receptors in the CNS causing inhibition of ascending pain pathways, altering
the perception of and response to pain; also inhibits the reuptake of norepinephrine and serotonin, which are neurotransmitters
involved in the descending inhibitory pain pathway responsible for pain relief (Grond 2004)
Pharmacokinetics
Onset of action: Immediate release: Within 1 hour; Peak effect: 2 to 3 hours
Distribution: Vd: IV: 2.6 L/kg (males); 2.9 L/kg (females)
Protein binding, plasma: ~20%
Metabolism: Extensively hepatic via demethylation (mediated by CYP3A4 and CYP2D6), glucuronidation, and sulfation; has
pharmacologically active metabolite formed by CYP2D6 (M1; O-desmethyl tramadol)
Bioavailability:
Immediate release: ~75%
Extended release: ~85% to 95% (as compared to immediate release)
Half-life elimination:
Immediate release: 6.3 ± 1.4 hours; active metabolite (M1): 7.4 ± 1.4 hours; prolonged in elderly
Extended-release:
Capsules: ~10 hours; active metabolite (M1): ~11 hours
Tablets: ~7.9 hours; active metabolite (M1): 8.8 hours.
Time to peak, plasma:
Immediate release: ~2 hours; active metabolite (M1): 3 hours
Extended release: ~4 to 12 hours; active metabolite (M1): ~5 to 15 hours
Excretion: Urine (~30% as unchanged drug; 60% as metabolites)
Pharmacokinetics: Additional Considerations
Altered kidney function: Decreased rate and extent of excretion.
Hepatic function impairment:
Immediate release: Metabolism is reduced in advanced cirrhosis, resulting in increased AUC and increased elimination half-life
(13 hours [tramadol], 19 hours [M1]).
Extended release: Exposure is decreased ~50% with increased severity of hepatic impairment.
Older adult: Maximum serum concentration is increased and elimination half-life prolonged.
Sex:
Immediate release: Women had a 12% higher peak tramadol concentration and a 35% higher area under the curve (AUC)
compared to men.
Extended release: AUC were somewhat higher in females than in males.
Note: Concentrations of tramadol were ~20% higher in “poor metabolizers” versus “extensive metabolizers,” while M1
concentrations were 40% lower.
Pricing: US
Capsule ER 24 Hour Therapy Pack (ConZip Oral)
100 mg (per each): $14.77
200 mg (per each): $19.35
300 mg (per each): $26.77
Capsule ER 24 Hour Therapy Pack (traMADol HCl ER Oral)
100 mg (per each): $9.18
200 mg (per each): $12.04
300 mg (per each): $16.65
Solution (Qdolo Oral)
5 mg/mL (per mL): $1.48
Solution (traMADol HCl Oral)
5 mg/mL (per mL): $2.38
Tablet, 24-hour (traMADol HCl ER (Biphasic) Oral)
100 mg (per each): $4.71
200 mg (per each): $7.78
300 mg (per each): $10.86
Tablet, 24-hour (traMADol HCl ER Oral)
100 mg (per each): $3.64
200 mg (per each): $6.02
300 mg (per each): $10.14
Tablets (traMADol HCl Oral)
50 mg (per each): $0.17 - $1.80
100 mg (per each): $1.93
Tablets (Ultram Oral)
50 mg (per each): $4.10
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided
when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine
the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate
any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer.
Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to
accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or
consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Brand Names: International

Adamon (CR, DO, GT, HN, NI, PA, PL, PY, SV);
Adolonta (ES);
Amanda (TH);
Analab (LK, MY, TH);
Betram (PH);
Biodalgic (FR);
Bongesic (CR,
DO, GT, HN, NI, PA, SV);
Calmador (AR);
Calmol (UY);
Contramal (BE, EG, FR, HU, IN, IT, TR);
Dolonil (BD);
Dolotral (PH);
Dolpar (ES);
Dolzam
(BE, LU);
Domadol (ET, ZW);
Durodor Retard (MX);
Durotram (AU, NZ);
E-Dol (ZW);
Kontram XL SR (KR);
Koridol (HK);
Lafedol (AR);
Lodam
(AU);
Lucidol (BD);
Lumidol (HR);
Mabron (AE, BH, CY, ET, IQ, IR, JO, KW, LB, LV, LY, MY, OM, SA, SG, SY, TH, YE);
Mabron SR (LV);
Mandolgin
(DK);
Manol (CL);
Monoalgic (FR);
Newtram (KR);
Noax (SI);
Noax Uno (PL);
Nobligan (NO, SE);
Nomal (QA);
Onetram (JP);
Orasic (ID);
Painlax (TW);
Paxilfar (PT);
Pengesic (HK, SG);
Pengesic SR 100 (ET);
Potendol SR (KR);
Predxal (VN);
Radol (ID);
Ramado Retard (KR);
Ramgic (TW);
Rivadol (EG);
Romadol (BD);
Sefmal (HK, SG, VN);
Seminac (ID);
Seminac Continus (ID);
Sensitram (BR);
Syndol (LK);
Tadol (SI);
Takadol (FR);
Tamolan (TH);
Theradol (NL);
Topalgic (FR);
Trabar (CH);
Trabilin (BB, BM, BS, BZ, CR, DO, GT, GY, HN, JM, NI, PA, SR, SV, TT);
Tradmin (ZW);
Tradol (ET, ZW);
Tradolan (AE, BH, CY, IQ, IR, JO, KW, LB, LY, OM, SA, SE, SY, YE);
Tradonal (BE, PH);
Tradorec (GB);
Tradorec XL
(IE);
Tralgit SR (SK);
Trama Inj (IL);
Tramacot (AR);
Tramada (MY);
Tramadex (IL);
Tramadol Slovakofarma (HU);
Tramadolor (LT);
Tramagetic
(NO);
Tramagit (DE);
Tramahexal (ZA);
Tramake (IE);
Tramal (AE, AT, AU, BF, BH, BJ, CH, CI, CL, CO, CR, CU, CY, CZ, DO, EC, EE, EG, ET, FI, GH,
GM, GN, GR, GT, HN, HR, IL, IQ, IR, JO, JP, KE, KW, LB, LR, LU, LY, MA, ML, MR, MT, MU, MW, NE, NG, NI, NL, NZ, OM, PA, PE, PH, PK, PL, PT,
QA, RU, SA, SC, SD, SK, SL, SN, SV, SY, TH, TN, TZ, UG, VE, YE, ZA, ZM);
Tramal Long (EC);
Tramal Retard (AE, BH, KW, LB, QA, SA);
Tramalgin
(BG);
Tramazac (BF, BJ, CI, ET, GH, GM, GN, IN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TH, TN, TZ, UG, ZM);
Tramcontin (CN);
Tramed (TW);
Tramedo (AU);
Tramica (ZW);
Tramol (LK);
Tramundin (DE);
Tramundin Retard (AE, KW);
Tramundin retard (BH);
Trasic (LK);
Trasik (ID);
TRD-Contin (IN);
Trexol (MX);
Tridol (KR);
Trol (BD);
Ultradol (BD);
Unitral (PH);
Urgendol (IN);
Vesnon-V (TH);
Zamadol (BR, GB);
Zamudol (FR);
Zodol (CL, PY);
Zudol (LK);
Zydol (AU, GB, IE);
Zydol XL (GB);
Zytram (ES);
Zytram XL SR (KR)
For country code abbreviations ( show table)
Use of UpToDate is subject to the Terms of Use.
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Tramadol: Drug information

Copyright 1978-2022 Lexicomp, Inc. All rights reserved.

ALERT: US Boxed Warning

Addiction, abuse, and misuse:

Opioid analgesic Risk Evaluation and Mitigation Strategy (REMS):

Life-threatening respiratory depression:

Accidental ingestion of tramadol, especially by children, can be fatal.

Neonatal opioid withdrawal syndrome:

Interactions with drugs affecting cytochrome P450 isoenzymes:

Risks from concomitant use with benzodiazepines or other CNS depressants:

Brand Names: Canada

Pain management, moderate to severe 

Pain management, moderate to severe:

Acute pain (eg, postoperative):

Chronic pain (alternative agent):

Opioid-naive patients not currently on tramadol immediate release:

Premature ejaculation (alternative agent) (off-label use):

Dosing: Kidney Impairment: Adult

Altered kidney function (Ref):

Hemodialysis, intermittent (thrice weekly): Dialyzable (7%):

Peritoneal dialysis: Dialyzability unknown (Davison 2014):

Dosing: Hepatic Impairment: Adult

Severe impairment: 50 mg every 12 hours.

Severe impairment (Child-Pugh class C): Avoid use.

(For additional information see "Tramadol: Pediatric drug information")

Acute pain: Immediate-release formulations:

Dosing: Kidney Impairment: Pediatric

Immediate release: Adolescents ≥17 years:

Extended release: Adolescents ≥18 years:

CrCl <30 mL/minute: Avoid use.

Dosing: Hepatic Impairment: Pediatric

Extended release: Adolescents ≥18 years:

Severe impairment (Child-Pugh class C): Avoid use.

Dosing: Older Adult

Elderly >75 years:

Immediate release: Maximum: 300 mg/day.

Extended release: Use with extreme caution.

Capsule Extended Release 24 Hour, Oral, as hydrochloride:

Generic: 100 mg, 150 mg [DSC], 200 mg, 300 mg

Solution, Oral, as hydrochloride:

Generic: 5 mg/mL (5 mL)

Tablet, Oral, as hydrochloride:

Ultram: 50 mg [DSC] [scored; contains corn starch]

Generic: 50 mg, 100 mg

Tablet Extended Release 24 Hour, Oral, as hydrochloride:

Generic: 100 mg, 200 mg, 300 mg

Generic Equivalent Available: US

Dosage Forms Considerations

100 mg: 25 mg (immediate release) and 75 mg (extended release)

200 mg: 50 mg (immediate release) and 150 mg (extended release)

300 mg: 50 mg (immediate release) and 250 mg (extended release)

Dosage Forms: Canada

Capsule Extended Release 24 Hour, Oral, as hydrochloride:

Tablet, Oral, as hydrochloride:

Tablet Extended Release 24 Hour, Oral:

Zytram XL: 75 mg [contains fd&c blue #2 (indigo carmine,indigotine)]

Zytram XL: 150 mg, 400 mg

Tablet Extended Release 24 Hour, Oral, as hydrochloride:

Ralivia: 100 mg, 200 mg, 300 mg

Tridural: 100 mg, 200 mg, 300 mg

Zytram XL: 100 mg, 200 mg, 300 mg